Polymeric nanoparticle has been known as useful means for delivering drug specifically only to the target site of the patient. In particular, since the nanoparticle made up of biodegradable polymer is slowly degraded in body and disappears, it shows good biocompatibility and is actually applied to nano-drugs. However, such nanoparticle of biodegradable polymer is unstable in an aqueous solution, and thus it is usually formulated in freeze-dried form which requires reconstitution in use. At that time, because of the nature of polymer, it takes longer time to redisperse the polymeric nanoparticle in an injection medium, etc. as compared with other freeze-dried injection formulation, resulting in difficulty in actual use.
Various methods such as dialysis, emulsification, organic solvent evaporation, etc. are known for preparing polymeric nanoparticle. Korean Laid-open Patent Publication No. 10-2009-0049239 discloses a method for preparing polymeric micelle by adding dropwise methotrexate dissolved in organic solvent to an aqueous solution of a copolymer of methoxy polyethylene glycol and chitosan, dialyzing the mixture solution with distilled water, and lyophilizing it. In addition, US 2009/0036389 A1 discloses a method comprising dissolving an amphiphilic block copolymer and a hydrophobic drug in a solvent which is immiscible with water and has a boiling point lower than that of water (i.e., acetonitrile, methanol, ethanol and acetone), adding a sufficient amount of water thereto in a constant rate to form micelle and then adding a lyophilization aid thereto, and removing the organic solvent and lyophilizing it. Furthermore, Korean Patent No. 10-0421451 discloses a method for preparing a drug-containing polymer micelle composition comprising a) dissolving an amphiphilic block copolymer and a hydrophobic drug in an organic solvent, wherein the amphiphilic block copolymer consists of a hydrophilic block (A) and a hydrophobic block (B) having a terminal group substituted with a functional group for improving affinity with the hydrophobic drug, and evaporating the organic solvent to prepare a drug-polymer matrix; b) dissolving the drug-polymer matrix in water to prepare an aqueous solution of polymer micelle wherein the drug is encapsulated; and c) lyophilizing the aqueous solution of polymer micelle and then sterilizing it. Korean Patent No. 10-0531269 and U.S. Pat. No. 7,311,901 B2 disclose a method for preparing polymeric nanoparticle by dissolving an amphiphilic block copolymer, a monovalent metal salt of a polylactic acid derivative and a hydrophobic drug together in a volatile organic solvent to prepare a homogenous solution, removing the organic solvent by distillation under reduced pressure, and adding thereto water to prepare a micelle mixture, and adding thereto divalent metal cation. However, none of the above patent literatures mentions specific lyophilization method and reconstitution time after the lyophilization.
WO 2003/005992 A1 suggests a method for improving redissolution ability after lyophilization by adding one or more stabilizing agents selected from the group consisting of saccharide and polyethylene glycol, to drug-containing polymer micelle consisting of an amphiphilic block copolymer. However, this method has a problem of necessarily adding polyethylene glycol (an extra excipient) to saccharide (a conventional lyophilization agent). It will be preferable if the redissolution ability can be improved only through specifically controlling lyophilization conditions without using such an extra excipient.
In addition, US 2014/0199286 A1, Japanese Laid-open Patent Publication No. 2008-231067 A and Japanese Laid-open Patent Publication No. 2007-526329 A disclose the influence of lyophilization cycle to lyophilized formulation. However, US 2014/0199286 A1 is directed to a formulation consisting of protein, sodium phosphate, mannitol, trehalose and polysorbate; JP 2008-231067 A is directed to a formulation consisting of a quinolone-based antibiotic and a pH controlling agent only; and JP 2007-526329 A is directed to a formulation containing protein, nucleic acid or virus. As such, these literatures are not directed to a polymeric formulation using an amphiphilic block copolymer, etc. No method of improving lyophilization method of polymeric formulation has been disclosed so far.